Baseline Characteristics and Early Blood Pressure Control in the CONVINCE Trial.

-Blood pressure (BP) control rates around the world are suboptimal. Part 2 of the National Health and Nutrition Educational Survey (NHANES) III indicates that only 27.4% of hypertensive Americans aged 18 to 74 years have a BP of <140/90 mm Hg. We wanted to assess BP control during the first 2 years and to describe the baseline characteristics of patients enrolled in the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Study, an international clinical trial that compares outcomes in hypertensive patients randomized to initial treatment with either controlled-onset extended-release verapamil or the investigator's choice of atenolol or hydrochlorothiazide. At randomization, BP was <140/90 mm Hg in only 20.3% of the 16 602 subjects (average+/-SD age 65.6+/-7.4 years; 56% women, 84% white/7% black/7% Hispanic). The average BP at enrollment was 148/85 mm Hg for patients taking BP medications (n=13 879) and 161/94 mm Hg for previously untreated patients (n=2723). After medication titration, with a transtelephonic computer that recommended an increase in the dose or number of antihypertensive agents whenever the BP was 140/90 mm Hg, 84.8% of the subjects attained the goal BP. During 2 years of treatment, BP control was maintained in 67% to 69% of the subjects (69% to 71% for systolic BP of <140 mm Hg and 90% for diastolic BP of <90 mm Hg). These data suggest that the control of systolic BP is more difficult than the control of diastolic BP. The US national goal of having 50% of hypertensives with a BP of <140/90 mm Hg may be achievable if a forced titration strategy is used. Interested investigators, free care and medications, and well-educated subjects may make the attainment of such a goal easier in the CONVINCE study than in the general population.

Effects of the chronotherapeutic delivery of verapamil on circadian blood pressure in African-American patients with hypertension.

OBJECTIVE: To evaluate the effects of COER-verapamil on circadian blood pressure (BP) and heart rate in African-American patients with hypertension. DESIGN: Retrospective pooled analyses of efficacy and tolerability data from three prospective, randomized, double-blind, placebo-controlled trials with COER-verapamil in hypertension. PATIENTS/PARTICIPANTS: Sixty-eight African-American patients with stages I-III hypertension (seated diastolic BP, 95-114 mm Hg) were randomized to receive placebo or treatment with 180-540 mg of COER-verapamil once daily at bedtime for 4 to 8 weeks. METHODS: Using ambulatory monitoring, efficacy was assessed by measuring change from baseline in systolic and diastolic BP, heart rate, and the heart rate-systolic pressure product during three time intervals: early morning (0600 to 1000), daytime (0800 to 2200), and nighttime (2200 to 0800). Changes also were compared to data from the non-African-American population. Adverse effects were tabulated at each visit. RESULTS: Mean changes from baseline in early-morning BP, heart rate, and rate-pressure product for patients treated with COER-verapamil were -13.8/-11.2 mm Hg, -6.2 beats/minute, and -1960 mm Hg-beats/min, respectively (P<0.01 for all parameters compared to placebo). Significant and similar reductions also were observed for daytime and nighttime BP, heart rate, and the rate-pressure product. The incidence of side effects in the COER-verapamil-treated patients was similar to placebo and the African-American patients had similar incidences to the non-African-American patients. CONCLUSIONS: The chronotherapeutic delivery of verapamil significantly reduced circadian BP, heart rate, and the rate-pressure product. The side effect profile of COER-verapamil was similar to that of placebo. Thus, this therapy for delivery of a heart-rate lowering calcium channel blocker is a useful antihypertensive strategy for African-American patients with hypertension.

Comparison of controlled-onset, extended-release verapamil with amlodipine and amlodipine plus atenolol on exercise performance and ambulatory ischemia in patients with chronic stable angina pectoris.

This multicenter, randomized, double-blind, parallel group, placebo lead-in, placebo-controlled study compared the antianginal and anti-ischemic effects of once-daily bedtime dosing of controlled-onset extended-release (COER-24) verapamil to a once-daily morning dosing of amlodipine +/- atenolol in patients with chronic stable angina. A total of 551 patients with exercise-induced myocardial ischemia and evidence of coronary artery disease were randomized to a 4-week, forced-dose titration treatment period with (1) COER-24 verapamil 240 mg titrated to 480 mg at bedtime (n = 173), (2) amlodipine 5 mg titrated to 10 mg/day (n = 149), (3) amlodipine 5 mg (titrated to 10 mg) plus atenolol 50 mg/day in the A.M. (n = 154), or (4) placebo (n = 75). Treadmill exercise tolerance testing (standard Bruce protocol), and 48-hour ambulatory electrocardiographic (Holter) monitoring were performed at the end of placebo lead-in and double-blind treatment. Each active treatment significantly improved symptom-limited exercise duration and time to moderate angina (p < or = 0.01 vs placebo). For patients with baseline ischemia, amlodipine resulted in a statistically significant increase in total duration of ischemic episodes compared with placebo, whereas COER-24 verapamil and amlodipine plus atenolol resulted in statistically significant decreases compared with placebo and amlodipine. Heart rate at onset of ischemic episodes and ST product were also significantly increased with amlodipine (p < 0.05) compared with either COER-24 or amlodipine plus atenolol. COER-24 and amlodipine alone or in combination with atenolol improved exercise capacity in patients with angina pectoris. COER-24 verapamil monotherapy or amlodipine plus atenolol combination therapy were more effective than amlodipine monotherapy in decreasing ambulatory myocardial ischemia, especially during the hours of 6 A.M. to 12 noon.

Rationale and design for the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial.

The Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial is a randomized, prospective, double-blind, parallel-group, two-arm, actively controlled, multicenter, international 5-year clinical trial involving 15,000 patients. CONVINCE will compare the incidence of fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, or cardiovascular-disease-related death in two antihypertensive treatment regimens. One treatment arm begins with controlled onset-extended release (COER)-verapamil, which has its major antihypertensive effect 6-12 hours after administration. The other arm (standard of care (SOC)) begins with either hydrochlorothiazide (HCTZ) or atenolol, one of which is preselected by the investigator for an individual patient prior to randomization. Secondary objectives include comparisons of the regimens for each of the components of the primary endpoint (separately), death or hospitalization related to cardiovascular disease, efficacy in lowering blood pressure to goal, primary events occurring between 6 am and noon, all-cause mortality, withdrawals from blinded therapy, cancer, and hospitalizations due to bleeding. Patients may be enrolled if they are hypertensive and at least 55 years of age and have an established second risk factor for cardiovascular disease. Initial medications include COER-verapamil (180 mg/d), HCTZ (12.5 mg/d), or atenolol (50 mg/d). Initial doses are doubled if blood pressure (BP) does not reach goal (systolic BP < 140 mm and diastolic BP < 90 mm Hg). If BP is not controlled by the higher dose of the initial medication, HCTZ is added to COER-verapamil, or the SOC choice not initially selected is added in the SOC arm. An ACE-inhibitor is recommended (although nearly any open-label medication is allowed) as the third step for patients whose BP is not adequately controlled or who have a contraindication to one of the two SOC medications. Patients take two sets of tablets daily, one in the morning and one in the evening. Although most patients switch from an established antihypertensive medication to randomized treatment, untreated patients with stages I-III hypertension (SBP between 140 and 190 or DBP between 90 and 110 mm Hg) are eligible. Outcomes are monitored by an independent Data and Safety Monitoring Board. Enrollment began during the third quarter of 1996, and follow-up is to be completed in the third quarter of 2002.

Comparison of effects of controlled onset extended release verapamil at bedtime and nifedipine gastrointestinal therapeutic system on arising on early morning blood pressure, heart rate, and the heart rate-blood pressure product.

We assessed the differential effects of a chronotherapeutic agent (controlled-onset extended release [COER] verapamil), administered at bedtime versus a conventional, homeostatic therapy (nifedipine gastrointestinal therapeutic system [GITS]) taken in the morning, on early morning and 24-hour blood pressure (BP), heart rate (HR), and the HR x systolic BP product. The study was a multicenter (n = 51), randomized, double-blind prospective clinical trial with a 10-week treatment period. Dose titration was performed by study investigators based on systolic and diastolic BP values at the doctor's office. Ambulatory BP monitoring was performed at placebo baseline, after 4 weeks of stable double-blind therapy, and at end of the study. Twenty-four-hour BP profiles were studied in 557 hypertensive patients. Changes in BP, HR, slope of the rate of rise of BP and HR, and the HR-systolic BP product during the 4 hours from 1 hour before to 3 hours after awakening were evaluated. The study was powered to show equivalence between the 2 regimens, predefined as a difference between treatment groups in mean change from baseline in early morning BP of +/- 5 mm Hg systolic and +/- 3 mm Hg diastolic. Changes in the early morning BP fell within the definition of equivalence for the 2 treatment strategies (-12.0/-8.2 mm Hg for COER-verapamil and -13.9/-7.3 mm Hg for nifedipine GITS). Changes in both the early morning HR and rate-pressure product were significantly greater following COER-verapamil therapy versus nifedipine GITS (HR, -3.8 beats/minute vs +2.6 beats/minute, p < 0.001 and HR-systolic BP product, -1,437 beats/min x mm Hg vs -703 beats/min x mm Hg, respectively, p < 0.001). Changes in ambulatory BP demonstrated clinically similar reductions for the awake period, but nifedipine GITS lowered systolic BP to a greater extent than COER-verapamil during sleep (-11.0 vs -5.8 mm Hg, p < 0.001). COER-verapamil and nifedipine GITS had equivalent effects (+/- 5/3 mm Hg) on early morning BP. In addition, both extended-release calcium antagonists effectively lowered 24-hour BP. However, COER-verapamil had greater effects than nifedipine GITS on early morning hemodynamics (HR, HR-systolic BP product, rate of rise of BP and HR) and lesser effects during sleep due to its intrinsic pharmacologic properties and chronotherapeutic delivery system.

Effects of controlled-onset extended-release verapamil on nocturnal blood pressure (dippers versus nondippers). COER-Verapamil Study Group.

Approximately 1 in 4 patients with systemic hypertension have a 24-hour blood pressure (BP) profile characterized by a blunted or absent nocturnal decline in pressure. We evaluated the effects of a chronotherapeutic delivery system of controlled-onset extended-release (COER) verapamil hydrochloride and placebo in 257 hypertensive patients according to their circadian BP pattern in an 8-week prospective, multicenter, randomized, and double-blind clinical trial. Patients were stratified into 193 dippers (>10% decline in BP during the period of 10 P.M. to 5 A.M. compared with the hours of 5 A.M. to 10 P.M.) and 64 nondippers (<10% decline in BP during nighttime). During daytime, placebo-subtracted BP was similarly decreased in dippers and nondippers by COER verapamil. During nighttime, the placebo increased nocturnal BP in dippers (baseline nocturnal BP, 133/78 mm Hg) by 3/3 +/- 2/2 mm Hg and reduced BP by -5/-3 +/- 2/2 mm Hg in nondippers (baseline nocturnal BP, 152/94 mm Hg) (p = NS between groups). After controlling for age, gender, ethnicity, and the regression to the mean observed on placebo for all doses, COER verapamil reduced nocturnal BP more in nondippers than dippers -5.8/-2.4 mm Hg, p <0.0001 for systolic BP and p = 0.09 for diastolic BP). Additionally, a significant dose-related reduction in systolic and diastolic nocturnal BP (r = 0.56, p <0.0001 for systolic BP and r = 0.62, p <0.0001 for diastolic BP) was observed with COER verapamil after controlling for baseline covariates. These data demonstrate that nocturnal BP is decreased by a greater extent in nondipper hypertensives than in dipper hypertensives following treatment with COER verapamil HCL.

The UVR wavelength dependence for lomefloxacin photosensitization of human skin.

Lomefloxacin is a new fluoroquinolone with effective broad-spectrum antimicrobial activity. However, in common with other structurally related drugs, skin photosensitization reactions have been reported. The wavelength dependence for such photosensitization has been investigated on the previously unexposed buttock skin of 12 normal healthy human volunteers of skin types I and II. Using geometric square root of 2 dose increments, baseline 24 h minimal erythema doses were assessed at 300, 320, 330, 340, 350 and 360 nm, and with broad-band UVA. In addition, dose-response curves were constructed for erythema as measured by a reflectance device. Subjects received single daily oral doses of 400 mg lomefloxacin at specified times for 4 days. At 2 h after the final dose, new areas of buttock skin were irradiated to assess changes in minimal erythema dose and erythema dose-response. Convolution of the erythema action spectra obtained pre- and on-drug with a terrestrial solar spectrum showed that, although the UVA sensitivity on-drug was enhanced, most of the erythemally effective solar energy was still in the UVB region. An action spectrum derived for lomefloxacin skin photosensitization showed peak activity at 320 nm, the same spectral region as that for maximal absorption of the drug. There was no evidence of skin photosensitization at 300 nm.

Evaluation of cycloserine in the treatment of Alzheimer's disease.

This multicenter study evaluated the efficacy and safety of cycloserine and measured its effects on explicit and implicit memory tests in patients with Alzheimer's disease (AD). Four hundred ten patients with AD, aged 50 years or older, were enrolled in this parallel-group, double-blind, placebo-controlled, randomized trial of 5, 15, or 50 mg cycloserine or placebo twice daily, and 403 entered the double-blind treatment phase. Two hundred sixty-five patients completed the entire 26-week treatment phase. There were no baseline differences among the four treatment groups. Cognitive Drug Research (CDR) efficacy assessments showed no differences between active treatments and placebo from baseline to study weeks 2, 6, 14, or 26. Patients receiving 15 mg of cycloserine improved significantly on one section of an implicit memory test. No differences among treatments were observed for any other assessment scales evaluated. The incidence and severity of adverse events were similar across treatment groups. Cycloserine was well tolerated but did not demonstrate consistent evidence of efficacy during the course of therapy. Higher doses may be necessary to achieve efficacy in the AD population and do not appear to be precluded by the adverse event profile seen in this study.

Photoreactions with a fluoroquinolone antimicrobial: evening versus morning dosing.

Quinolone antimicrobials absorb ultraviolet radiation and, with appropriate drug concentrations, may cause photoreactions. Photoreactions have been reported for several quinolones, including lomefloxacin, a difluorinated quinolone antimicrobial. This study was designed to determine whether the interval between administration of lomefloxacin and exposure to ultraviolet A (UVA) light would affect skin responses. The minimal erythema dose (MED) and severity of local reactions were the main parameters of evaluation. Exposure to UVA radiation 2 hours after morning dosing caused an increase in skin sensitivity as assessed by changes in MED (p < 0.05). No changes were observed with exposure 16 hours after evening dosing (p = 1.00). Edema and blisters at the radiation sites were observed in only the morning dosing group. A significant negative correlation was observed between lomefloxacin plasma concentrations and change MEDs (r = -0.72; p < 0.05). An evening dosing strategy may minimize the risk of phototoxic effects.

Evaluation of multiple doses of milacemide in the treatment of senile dementia of the Alzheimer's type.

A multicenter, double-blind, placebo-controlled, parallel group study was conducted to assess the safety and efficacy of three doses of milacemide in the treatment of patients with senile dementia of the Alzheimer type of mild to moderate severity. Patients were randomly assigned to receive one of three dosages of milacemide (400, 800, or 1200 mg/day) or placebo for 4 weeks followed by a single-blind 4-week placebo period. One hundred forty-eight men and women older than 50 years of age were enrolled, and 129 patients completed the study. The differences among treatment groups were not statistically different with respect to total scores on the Alzheimer's Disease Assessment Scale or any items and subscales that were examined, nor were significant differences on the Clinical Global Impression Scale found. Clinically significant increases in liver function tests, specifically aspartate aminotransferase and alanine aminotransferase (AST and ALT), were reported for five of the patients receiving milacemide, requiring their withdrawal from the study.

Misoprostol versus antacid titration for preventing stress ulcers in postoperative surgical ICU patients.

Bleeding from gastroduodenal lesions is a potentially life-threatening complication in patients subjected to overwhelming physiologic stress. Titration of gastric contents with antacid was the first prophylactic treatment regimen proved to decrease the incidence of bleeding and remains the standard by which other methods are compared. We designed a prospective double-blind, double-placebo study comparing the effectiveness of antacid titration with fixed doses of a synthetic prostaglandin E1 analog (misoprostol) for preventing stress gastritis and bleeding. To assess the success of each treatment regimen, we did endoscopic examinations before operation, 72 hours after operation, and after the patient had completed the study. A total of 281 patients entered the study (140 misoprostol, 141 antacid). The two groups were comparable with respect to preoperative parameters and type of operation. We found no statistically significant differences between the two treatment groups concerning upper gastrointestinal tract lesions or serious adverse effects. No clinically evident upper gastrointestinal hemorrhage occurred in either group. Mean gastric pH, measured at two-hour intervals during the initial 72 hours, was maintained at 4.0 or higher in both groups. We conclude that fixed-dose misoprostol is as effective as intensive antacid titration in preventing stress ulcers and bleeding in surgical ICU patients.

The anticonvulsant and CNS activity of N-butyryl-N-butylurea in mice.

As a further extension of our studies related to CNS activity of substituted butylureas, a number of derivatives of butylurea were synthesized. Among these a derivative of n-butylurea, N-butyryl-N-butylurea (NBNB) was prepared by acylation of n-butylurea with butyryl chloride in pyridine. The compound was found to possess considerable sedative-hypnotic action. Sleeping time of pentobarbital and barbital was significantly potentiated by NBNB. The compound also exhibited moderate anti-tremorine action and produced significant reduction in the activity ratio for Treadmill experiments. Significant anticonvulsive activity of NBNB was observed against strychnine, pentetrazole and supramaximal electroshock-induced convulsions. In addition to protection against tonic convulsions, the animals were also protected against strychnine and pentetrazole lethality.

Synthesis and neuropharmacology of cyclobutanecarbonylureas.

Ten urea derivatives of cyclobutanecarboxylic acid were synthesized and examined for general CNS depressant properties, barbiturate potentiation, myorelaxant, antitremorine and anticonvulsant potencies. Water solubility seems to play an important part in the activity of these compounds. However, lipid solubility also plays a part as activity determinant. 1-Cyclo-butanecarbonyl-3-ethylthiourea appears to be the most active CNS depressant, whereas the parent compound, cyclobutanecarbonylurea, is the most active barbiturate potentiator. Cyclobutanecarbonylurea, 1-cyclobutanecarbonyl-3-n-butylurea and 1-cyclobutanecarbonyl-3-(2,4-xylyl)urea appear to be the most active myorelaxants, while 1-cyclobutanecarbonyl-3-n-butylurea and 1-cyclobutanecarbonyl-3-(1-adamantyl)urea are the most active against pentylenetetrazole-induced convulsions. Cyclobutanecarbonylurea, 1-cyclobutane-carbonyl-3-n-butylurea, 1-cyclobutancarbonyl-3-cyanoacetylurea, 1-cyclobuta-necarbonyl-3-(1-adamantyl)urea and 1-cyclobutanecarbonyl-3-(2,4-xylyl)urea are also slightly active oxotremorine antagonists. None of the compounds possess significant analgesic activity.

Hypotensive agent from Cynomorium coccineum.

The Iranian plant Cynomorium coccineum was investigated and found to possess significant blood pressure lowering activity in the dog. Extensive chemical isolation and fractionation has revealed that the depressor components were mainly present in the fresh juice of the plant. The fractions, by various organic solvents, of the dried powdered plant lacked significant depressor activity. However, the fresh juice of the plant as well as the water soluble fractions of the fresh juice exhibited strong depressor activity. Spectroscopic metal analysis and infrared and Mass spectra of the active fractions seem to suggest the inorganic nature of these fractions with very low carbon and hydrogen contents which are present, perhaphs, in some special molecular arrangement that becomes disrupted due to sensitivity to the analytical procedures employed.

Atrio-ventricular conduction defects and arrhythmias by selective perfusion of the A-V conduction system in the canine heart.

Ligation and cannulation of the anterior septal artery in 43 canine hearts caused changes in ST-T segment of the electrocardiogram in all animals. Perfusions of 0.9% NaCl, one to ten micrograms of acetylcholine, isoproterenol, epinephrine and norepinephrine, into the anterior septal artery caused variations in the ECG ranging from exaggerated ST-T changes to PR prolongation, ectopic atrial, nodal and ventricular beats, A-V blocks and dissociations, atrial fibrillation and ventricular fibrillation. The response seemed to be somewhat specific for cholinergic versus adrenergic agents showing more conduction defects by the former against greater changes in automaticity by the latter agents.

Some aspects of the neuropharmacology of phenylurea.

The neuropharmacology of phenylurea was studied. The compound is a potent sedative hypnotic agent with a fairly good margin of safety. It produced significant motor incoordination and behavioral changes in sub-sedative doses, thus suggesting that it acts on the areas of the brain which control motor coordination (neurological deficit) and spontaneous motor movements (awareness of environment). The activity pattern of phenylurea as measured on the rotarod treadmill was identical with that of an ataractic drug, meprobamate, and different from that of the sedative drug, 2-ethylcrotonylurea (ectylurea). It exhibited significant meprobamate-like antistrychnine (myorelaxant) activity, and at high doses only, anticonvulsant activity (pentetrazole antagonism). Phenylurea also protected mice against tremorine-induced tremors. A sub-sedative dose of phenylurea significantly prolonged pentobarbital sleeping time.

Pharmacology of Quercus infectoria.

The galls of Quercus infectoria (Fagaceae), a commonly available plant in Iran, were studied pharmacologically. Two fractions were employed, a dried acetone-treated methanol extract dissolved in water (Fraction A) and a subfraction prepared by chloroform-methanol extraction (Fraction B). Fraction A was active as an analgesic in rats and significantly reduced blood sugar levels in rabbits. Fraction B had CNS depressant activity. Data obtained with a treadmill indicated a decreased activity ratio by Fraction B, suggesting a possible interference in motor coordination. It potentiated the barbiturate sleeping time significantly without changing the onset time or the loss of the righting reflex. In addition, Fraction B exhibited a moderate antitremorine activity by causing a delay in the onset and a decrease in the severity of tremorine-induced tremors. The local anesthetic action of Fraction B was evident due to the complete blockade of the isolated frog sciatic nerve conduction.

Therapy and prophylaxis of Pneumocystis carinii pneumonia.

Pentamidine isethionate and sulfadoxine plus pyrimethamine are excellent therapeutic agents in experimental and hypoergic, hypoimmune pneumocystosis as well as in focal interstitial plasma cell pneumonia (IPCP) in infants. Their effectiveness is seriously limited in cases in which either a diffuse massive plasma cell exudate has been established or in adults in whom the phagocytic and resorptive facility is depressed. Infantile pneumocystosis leading to IPCP can be completely prevented by proper feeding and care of the patient or prophylactic drug therapy with sulfadoxine-pyrimethamine. Similar measures should be taken for adult patients at risk in hospitals where pneumocystosis is frequent or when pneumocystosis has been recently diagnosed.